1) Hubble:

Cheaper to launch a whole new one each time than waste money on manned servicing. (And at least the lens would have been ground properly for the second and third ones...)

2) Bigger ET

By all means go to a larger ET with more fuel capacity. Instead of dropping them to burn-up, launch to orbit and use as the core of a new space station. However, you need a goal for doing this - either the Moon or Mars. (or both, sequentially)

3) Stack geometry

DON'T use a winged orbiter. It leads to stupid stack geometries that are aerodynamically inefficient and compromise mission safety (14 dead so far due to this)

4) Landing

Don't fit wings, or aero engines, or other heavy things purely to give you landing flexibility. Instead, use a dumb capsule with thick heatshields and invest in a few pursuit aircraft, VTOL's and helicopters to allow you to reach the crew quickly. A steerable parafoil may give sufficient cross-range flexibility to avoid major obstacles like cities or lakes.

5) Goals

As alluded above, have a genuine goal, other than playing in weightlessness. Perhaps test out architecture and life support for a Mars mission, with spin gravity.

Stick to this goal determinedly and stay in budget, on time, and publicly visible.

6) Support

Above all, work to build and maintain support from the taxpaying public and both houses of government, otherwise the plug will be pulled before you get anywhere.

Otherwise, it's a waste of everyone's time, money, and effort.

Personally, I think the ISS should be abandoned until such time as safe and reliable transport is available, and the goals of space exploration are made clearer and communicated better.